Type 1 diabetes (T1D) is a disorder that arises following the autoimmune destruction of insulin producing pancreatic cells. Previous studies, including many emanating from this P01 in previous years, have demonstrated that individuals with T1D display a number of immunological abnormalities (e.g., frequency and function of iNKT cells, maturation of dendritic cells, interactions between regulatory and effector T cells, cytokin production, etc.). However, the contribution of specific genes to this process as well as an informative description of the interactions between specialized cells and molecules of the innate and adaptive immune systems that lead to a loss of tolerance to cells and eventually T1D remains unclear. Thus, our goal in seeking renewal of this P01 is to elucidate the mechanisms by which genes; IFIH1,TYK2 (investigated in Project 1) and IL18RAP, TLR8 (Project 2) impart immunoregulatory abnormalities that result in aberrant iNKT development, inflammatory antigen presenting cells, expansion of autoreactive lymphocytes, and defective regulatory/effector mechanisms in T cells. These activities will collectively test our overall hypothesis that defects n these systems are key to engender the autoimmune destruction of pancreatic cells that result in T1D. Indeed, this P01 will examine this hypothesis through two separate but highly interactive Projects that share data, use innovative technologies, and assess samples from extremely valuable human subjects with or at various levels of risk for T1D. This latter notion includes analysis of tissue samples from the Network for Pancreatic Organ Donors with Diabetes (nPOD), a heretofore effort unseen in research within the T1D community (i.e., availability of high quality pancreatic and lymphoid tissues from humans). These Projects will be supported by two Core facilities: Core A - Administrative Core; Core B - Biorepository, Immunology and Pathology Core. If successful, these efforts could dramatically improve prospects for the development of an effective therapeutic capable of preventing and/or reversing T1D, as well as to provide novel biomarkers for disease susceptibility and autoimmune activity associated with the disease.